Compositions comprising 15-hepe and methods of using the same

ABSTRACT

The present invention relates to the compositions comprising 15-HEPE and methods of treatment relating to same.

PRIORITY CLAIM

This application claims priority to U.S. Provisional Application No.62/269,280, filed Dec. 18, 2015, which is incorporated herein byreference in its entirety.

TECHNICAL FIELD

The present disclosure provides compositions, formulations and methodsof treating or preventing a disease by administering a pharmaceuticalcomposition comprising 15-hydroxyeicosapentaenoic acid (also referred toas 15-HEPE or 15-OHEPA) to a subject in need thereof.

SUMMARY

In various embodiments, the invention provides compositions andformulations comprising 15-hydroxy eicosapentaenoic acid (hereinafter“15-HEPE”) and methods of treating diseases and disorders using thesame. The compositions and formulations disclosed herein may be used inthe treatment of liver disease, arthritis, fibrosis, idiopathicpulmonary fibrosis, impaired insulin sensitivity, psoriasis, cancer(e.g. melanoma), neurodegenerative disorders (e.g. Huntington'sdisease), inflammatory diseases, adipocyte differentiation, fertility orreproduction issues, pain, obesity, and their sequelae, among otherdiseases and disorders.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present technology can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present technology.

FIG. 1 graphically illustrates mean plasma concentrations of15-Hydroxy-Eicosapentaenoic Acid Ethyl Ester [15(S)-HEPE] following asingle oral dose of 100 mg, 500 mg, 1000 mg, and 2000 mg DS102, underfasted conditions.

FIG. 2 graphically illustrates mean plasma 15(S)-HEPE concentrationsfollowing a single oral dose of 500 mg DS102 (15-HEPE) under fasted andfed conditions.

FIG. 3 graphically illustrates mean plasma 15(S)-HEPE concentrationsfollowing multiple oral QD doses of 500 mg and 1000 mg for 28 days,under fasted conditions, at day 1 of 28.

FIG. 4 graphically illustrates mean plasma 15(S)-HEPE concentrationsfollowing multiple oral QD doses of 500 mg and 1000 mg for 28 days,under fasted conditions, at day 14 of 28.

FIG. 5 graphically illustrates mean plasma 15(S)-HEPE concentrationsfollowing multiple oral QD doses of 500 mg and 1000 mg for 28 days,under fasted conditions, at day 28 of 28.

DETAILED DESCRIPTION

In various embodiments, the invention provides compositions andformulations comprising 15-HEPE and methods of treating diseases anddisorders using the same.

As used herein, “15-HEPE” is 15-Hydroxy-eicosa-5,8,11,13,17-pentaenoicacid. 15-HEPE, also occasionally referred to as 15-OHEPA, can besynthesized from eicosapentaenoic acid (“EPA,”eicosa-5,8,11,14,17-pentaenoic acid or 20:5n-3), an omega-3 fatty acidaccording to methods known in the art. As used herein, the term“15-HEPE” refers to 15-HEPE in its free acid form (e.g,15-hydroxy-eicosa-5,8,11,13,17-pentaenoic acid) and/or apharmaceutically acceptable ester, conjugate or salt thereof, ormixtures of any of the foregoing. A derivative of 15-HEPE may be usedinstead, though this does not include any derivative compound missingthe hydroxy group of 15-HEPE. In some embodiments, the 15-HEPE is usedin the free acid form. Alternatively, pharmaceutically acceptable estersor salts of 15-HEPE are used in the invention. In some embodiments, the15-HEPE is in the form of a C₁₋₄ alkyl ester such as methyl ester orethyl ester form.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of 15-HEPE.The 15-HEPE may be the sole significant active ingredient in thatcomposition and in the methods and uses as stated herein. The 15-HEPEmay be the sole active ingredient. Alternatively, the 15-HEPE may becombined for co-formulation or co-administration with other agents.

In one embodiment, 15-HEPE or a composition comprising 15-HEPE isadministered to a fed subject. A “fed subject” or a subject in a “fedstate” herein refers to a subject who has had a meal within theproceeding 4 hours.

15-HEPE is a chiral molecule and may be used in the (S)- or(R)-enantiomeric form, or as a racemic mixture. Used herein, “15-HEPE”includes all such forms, with no limitation as to stereospecifcity. Inanother embodiment, the 15-HEPE comprises the (S) form:15(S)-Hydroxy-(5Z,8Z,11Z,13E,17Z)-eicosapentaenoic acid. In someembodiments, the 15-HEPE may be used in the form of the ethyl ester. Inother embodiments, the 15-HEPE may be used as the free acid.

The present invention further provides a pharmaceutical composition fororal delivery, comprising 15-HEPE. That composition may comprise apharmaceutically acceptable excipient. The 15-HEPE may be in any form asdiscussed herein. The 15-HEPE may be present from about 50 mg to about3000 mg.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice of the present invention, suitable methods and materials aredescribed below. All publications, patent applications, patents, andother references mentioned herein are expressly incorporated byreference in their entirety. In cases of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples described herein are illustrative only,and are not intended to be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description. While the present invention is capableof being embodied in various forms, the description below of severalembodiments is made with the understanding that the present disclosureis to be considered as an exemplification of the invention, and is notintended to limit the invention to the specific embodiments illustrated.Headings are provided for convenience only and are not to be construedto limit the invention in any manner. Embodiments illustrated under anyheading may be combined with embodiments illustrated under any otherheading.

The use of numerical values in the various quantitative values specifiedin this application, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about.” In this manner,slight variations from a stated value can be used to achievesubstantially the same results as the stated value. Also, the disclosureof ranges is intended as a continuous range including every valuebetween the minimum and maximum values recited as well as any rangesthat can be formed by such values. Also disclosed herein are any and allratios (and ranges of any such ratios) that can be formed by dividing arecited numeric value into any other recited numeric value. Accordingly,the skilled person will appreciate that many such ratios, ranges, andranges of ratios can be unambiguously derived from the numerical valuespresented herein and in all instances such ratios, ranges, and ranges ofratios represent various embodiments of the present invention.

15-Hydroxy Eicosapentaenoic Acid

In one embodiment, compositions of the invention comprise 15-HEPE as anactive ingredient. 15-HEPE is the abbreviation for 15-Hydroxyeicosapentaenoic acid, a metabolite of eicosapentaenoic acid (EPA) thatcan be synthesized via methods known in the art, such as exposure ofeicospentaenoic acid to the enzyme 15-lipoxygenase. As used herein, theterm “15-HEPE” refers to 15-HEPE in its free acid form (e.g., 15-Hydroxyeicosapentaenoic acid) and/or a pharmaceutically acceptable ester,conjugate or salt thereof, or mixtures of any of the foregoing. Aderviative of 15-HEPE may be used instead, though this does not includeany derivative compound missing the hydroxy group of 15-HEPE. The term“pharmaceutically acceptable” in the present context means that thesubstance in question does not produce unacceptable toxicity to thesubject or interaction with other components of the composition.

In one embodiment, the 15-HEPE is in the form of an ester (also referredto herein as E-15-HEPE or ethyl-15-HEPE). In another embodiment, the15-HEPE comprises a C₁-C₅ alkyl ester of 15-HEPE. In another embodiment,the 15-HEPE comprises 15-HEPE methyl ester, 15-HEPE propyl ester, or15-HEPE butyl ester. In still another embodiment, the 15-HEPE comprisesthe optically active 15(S)-Hydroxy-(5Z,8Z,11Z,13E,17Z)-eicosapentaenoicacid. This isomer may be used in any of the forms discussed above.

In another embodiment, the 15-HEPE comprises lithium 15-HEPE, mono, di-or triglyceride 15-HEPE or any other ester or salt of 15-HEPE, or thefree acid form of 15-HEPE.

In various embodiments, the invention provides pharmaceuticalcompositions, for example orally deliverable compositions, comprising15-HEPE. In one embodiment, the compositions comprise a therapeuticallyeffective amount of 15-HEPE. In one embodiment, the pharmaceuticalcomposition comprises about 0.1% to about 99%, about 1′)/0 to about 95%,about 5% to about 90% by weight of 15-HEPE.

In one embodiment, the pharmaceutical composition comprises about atleast about 70%, at least about 80% or at least about 90%, by weight, of15-HEPE. In one embodiment, the pharmaceutical composition comprises atleast about 50%, at least about 60%, at least about 70%, at least about80% or at least about 90%, by weight of 15-HEPE.

In another embodiment, 15-HEPE is present in a composition of theinvention in an amount of about 1 mg to about 10,000 mg, 25 mg to about7500 mg, about 25 mg to about 5000 mg, about 50 mg to about 5000 mg,about 50 mg to about 3000 mg, about 75 mg to about 2500 mg, or about 100mg to about 1000 mg, for example about 25 mg, about 50 mg, about 75 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg,about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg,about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg,about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg,about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg,about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg,about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg,about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg,about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg,about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg,about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475mg, or about 2500 mg.

In one embodiment, 15-HEPE present in a composition of the inventioncomprises at least 90% by weight 15-HEPE (as the term “15-HEPE” isdefined and exemplified herein). 15-HEPE compositions can comprise evenhigher purity 15-HEPE, for example at least 95% by weight 15-HEPE or atleast 97% by weight 15-HEPE, wherein the 15-HEPE is any form of 15-HEPEas set forth herein. The purity of 15-HEPE can further be defined (e.g.impurity profile) by any of the descriptions of 15-HEPE provided herein.

Above are discussed the amounts of the 15-HEPE in the pharmaceuticalcomposition and their purity. The nature of the essential fatty acidsand their synthesis is such that the 15-HEPE composition may includemoieties from other essential fatty acids in the essential fatty acidmetabolic cascade.

In one embodiment, a composition of the invention contains not more thanabout 10%, not more than about 9%, not more than about 8%, not more thanabout 7%, not more than about 6%, not more than about 5%, not more thanabout 4%, not more than about 3%, not more than about 2%, not more thanabout 1° A, or not more than about 0.5%, by weight of other omega-3fatty acids including alpha linolenic acid, stearidonic acid,docosahexaenoic acid (DHA) or derivatives thereof. In other embodimentsthere is substantially no, or no such other omega-3 fatty acids present.

In another embodiment, 15-HEPE represents at least about 60%, at leastabout 70%, at least about 80%, at least about 90%, at least about 95%,at least about 97%, at least about 98%, at least about 99%, or 100%, byweight, of all fatty acids present in a composition of the invention.

There may be present some residual eicosapentaenoic acid from thesynthesis of the 15-HEPE. There may be, not more than about 10%, notmore than about 9%, not more than about 8%, not more than about 7%, notmore than about 6%, not more than about 5%, not more than about 4%, notmore than about 3%, not more than about 2%, not more than about 1° A, ornot more than about 0.5%, by weight EPA. Alternatively, there issubstantially no, or some EPA in a form which has not been modified tothe hydroxyl-form.

Dosage Forms

A composition for use in accordance with the disclosure can beformulated as one or more dosage units. The terms “dose unit” and“dosage unit” herein refer to a portion of a pharmaceutical compositionthat contains an amount of a therapeutic agent suitable for a singleadministration to provide a therapeutic effect. Such dosage units may beadministered one to a plurality (i.e. 1 to about 10, 1 to 8, 1 to 6, 1to 4 or 1 to 2) of times per day, or as many times as needed to elicit atherapeutic response.

In some embodiments, compositions of the invention are in the form oforally deliverable dosage forms or units. Non-limiting examples ofsuitable dosage forms include tablets (e.g. suspension tablets, bitesuspension tablets, rapid dispersion tablets, chewable tablets, etc),caplets, capsules (e.g. a soft or a hard gelatin capsule or HPMCcapsule), lozenges, sachets, cachets, troches, pellets, suspension,elixirs, syrups or any other solid dosage form reasonably adapted fororal administration. The terms “oral delivery” and “oral administration”herein include any form of delivery wherein the agent or composition isplaced in the mouth of the subject under treatment, whether swallowed ornot. This therefore includes buccal and sublingual administration, aswell as esophagael administration.

Alternatively, compositions of the invention can also be formulated forrectal, topical, or parenteral (e.g. subcutaneous, intramuscular,intravenous and intradermal or infusion) delivery.

In discussing the amount of 15-HEPE in a composition of the invention,this may be split over several dosage forms. There is a limit as to thesize for oral administration. If a subject is to be administered 1 to 4g 15-HEPE a day, this may be by up to 4 capsules, each providing 1 g of15-HEPE.

Compositions of the invention can be in the form of liquid dosage formsor dose units to be imbibed directly or they can be mixed with food orbeverage prior to ingestion. Non-limiting examples of suitable liquiddosage forms include solutions, suspensions, elixirs, syrups, liquidaerosol formulations, and the like.

In another embodiment, compositions of the invention comprise one ormore pharmaceutically acceptable excipients. The term “pharmaceuticallyacceptable excipient” herein means any substance, not itself atherapeutic agent, used as a carrier or vehicle for delivery of atherapeutic agent to a subject or added to a pharmaceutical compositionto improve its handling or storage properties or to permit or facilitateformation of a unit dose of the composition, and that does not produceunacceptable toxicity or interaction with other components in thecomposition. By way of example only, a pharmaceutical compositionaccording to the present disclosure may comprise one or more of:antioxidants, surfactants, preservatives, flavouring agents,co-solvents, viscosity aids, suspension aids, and lipophilic phases.

In one embodiment, the pharmaceutical composition comprises one or moreantioxidants such as ascorbic acid, palmitic acid, ascorbyl palmitate,α-tocopherol, idebenone, ubiquinone, ferulic acid, coenzyme Q10,lycopene, green tea, catechins, epigallocatechin 3-gallate (EGCG), greentea polyphenols (GTP), silymarin, coffeeberry, resveratrol, grape seed,pomegranate extracts, genisten, pycnogenol, niacinamide, and the like.In one embodiment, the pharmaceutical composition comprises about 0.01wt. % to about 2 wt. % of an antioxidant, for example about 0.01 wt. %,about 0.02 wt. %, about 0.03 wt. %, about 0.04 wt. %, about 0.05 wt. %,about 0.06 wt. %, about 0.07 wt. %, about 0.08 wt. %, about 0.09 wt. %,about 0.1 wt. %, about 0.11 wt. %, about 0.12 wt. %, about 0.13 wt. %,about 0.14 wt. %, about 0.15 wt. %, about 0.16 wt. %, about 0.17 wt. %,about 0.18 wt. %, about 0.19 wt. %, about 0.2 wt. %, about 0.21 wt. %,about 0.22 wt. %, about 0.23 wt. %, about 0.24 wt. %, about 0.25 wt. %,about 0.26 wt. %, about 0.27 wt. %, about 0.28 wt. %, about 0.29 wt. %,about 0.3 wt. %, about 0.31 wt. %, about 0.32 wt. %, about 0.33 wt. %,about 0.34 wt. %, about 0.35 wt. %, about 0.36 wt. %, about 0.37 wt. %,about 0.38 wt. %, about 0.39 wt. %, about 0.4 wt. %, about 0.41 wt. %,about 0.42 wt. %, about 0.43 wt. %, about 0.44 wt. %, about 0.45 wt. %,about 0.46 wt. %, about 0.47 wt. %, about 0.48 wt. %, about 0.49 wt. %,about 0.5 wt. %, about 0.51 wt. %, about 0.52 wt. %, about 0.53 wt. %,about 0.54 wt. %, about 0.55 wt. %, about 0.56 wt. %, about 0.57 wt. %,about 0.58 wt. %, about 0.59 wt. %, about 0.6 wt. %, about 0.61 wt. %,about 0.62 wt. %, about 0.63 wt. %, about 0.64 wt. %, about 0.65 wt. %,about 0.66 wt. %, about 0.67 wt. %, about 0.68 wt. %, about 0.69 wt. %,about 0.7 wt. %, about 0.71 wt. %, about 0.72 wt. %, about 0.73 wt. %,about 0.74 wt. %, about 0.75 wt. %, about 0.76 wt. %, about 0.77 wt. %,about 0.78 wt. %, about 0.79 wt. %, about 0.8 wt. %, about 0.81 wt. %,about 0.82 wt. %, about 0.83 wt. %, about 0.84 wt. %, about 0.85 wt. %,about 0.86 wt. %, about 0.87 wt. %, about 0.88 wt. %, about 0.89 wt. %,about 0.9 wt. %, about 0.91 wt. %, about 0.92 wt. %, about 0.93 wt. %,about 0.94 wt. %, about 0.95 wt. %, about 0.96 wt. %, about 0.97 wt. %,about 0.98 wt. %, about 0.99 wt. %, about 1 wt. %, about 1.1 wt. %,about 1.2 wt. %, about 1.3 wt. %, about 1.4 wt. %, about 1.5 wt. %,about 1.6 wt. %, about 1.7 wt. %, about 1.8 wt. %, about 1.9 wt. %, orabout 2 wt. % of the one or more antioxidant.

Therapeutic Methods

The compositions and formulations disclosed herein may be used in thetreatment of a liver disease, arthritis, fibrosis, idiopathic pulmonaryfibrosis, impaired insulin sensitivity, psoriasis, cancer (e.g.melanoma), neurodegenerative disorders (e.g. Huntington's disease),inflammatory diseases, adipocyte differentiation, fertility orreproduction issues, pain, obesity, and their sequelae.

In one embodiment, the present disclosure provides a method of treatingand/or preventing impaired insulin sensitivity in a subject, the methodcomprising administering to the subject an effective amount of acomposition comprising 15-HEPE. In some embodiments, the method furthercomprises determining that the subject is sensitive to insulin and/or isat risk of developing insulin sensitivity before administering thecomposition comprising 15-HEPE.

In one embodiment, the present disclosure provides a method of treatingand/or preventing psoriasis in a subject, the method comprisingadministering to the subject an effective amount of a compositioncomprising 15-HEPE. In some embodiments, the method further comprisesdetermining that the subject has psoriasis and/or is at risk ofdeveloping psoriasis before administering the composition comprising15-HEPE.

In one embodiment, the present disclosure provides a method of treatingand/or preventing cancer in a subject, the method comprisingadministering to the subject an effective amount of a compositioncomprising 15-HEPE. In some embodiments, the method further comprisesdetermining that the subject has cancer and/or is at risk of developingcancer before administering the composition comprising 15-HEPE. In someembodiments, the cancer is a skin cancer. In some embodiments, the skincancer is melanoma.

In one embodiment, the present disclosure provides a method of treatingand/or preventing a neurodegenerative disorder in a subject, the methodcomprising administering to the subject an effective amount of acomposition comprising 15-HEPE. In some embodiments, the method furthercomprises determining that the subject has a neurodegenerative disorderand/or is at risk of developing a neurodegenerative disorder beforeadministering the composition comprising 15-HEPE. In some embodiments,the neurodegenerative disorder is Huntington's disease.

In one embodiment, the present disclosure provides a method of treatingand/or preventing an inflammatory disease in a subject, the methodcomprising administering to the subject an effective amount of acomposition comprising 15-HEPE. In some embodiments, the method furthercomprises determining that the subject has an inflammatory diseaseand/or is at risk of developing an inflammatory disease beforeadministering the composition comprising 15-HEPE.

In one embodiment, the present disclosure provides a method of treatingand/or preventing an adipocyte differentiation disorder in a subject,the method comprising administering to the subject an effective amountof a composition comprising 15-HEPE. In some embodiments, the methodfurther comprises determining that the subject has an adipocytedifferentiation disorder and/or is at risk of developing an adipocytedifferentiation disorder before administering the composition comprising15-HEPE.

In one embodiment, the present disclosure provides a method of treatingand/or preventing fertility or reproduction issues in a subject, themethod comprising administering to the subject an effective amount of acomposition comprising 15-HEPE. In some embodiments, the method furthercomprises determining that the subject has fertility or reproductionissues and/or is at risk of developing fertility or reproduction issuesbefore administering the composition comprising 15-HEPE.

In one embodiment, the present disclosure provides a method of treatingand/or preventing pain in a subject, the method comprising administeringto the subject an effective amount of a composition comprising 15-HEPE.In some embodiments, the method further comprises determining that thesubject has pain and/or is at risk of developing pain beforeadministering the composition comprising 15-HEPE.

In one embodiment, the present disclosure provides a method of treatingand/or preventing obesity in a subject, the method comprisingadministering to the subject an effective amount of a compositioncomprising 15-HEPE. In some embodiments, the method further comprisesdetermining that the subject is obese and/or is at risk of becomingobese before administering the composition comprising 15-HEPE.

In one embodiment, the present disclosure provides a method of treatingand/or preventing idiopathic pulmonary fibrosis in a subject, the methodcomprising administering to the subject an effective amount of acomposition comprising 15-HEPE. In some embodiments, the method furthercomprises determining that the subject has idiopathic pulmonary fibrosisand/or is at risk of developing idiopathic pulmonary fibrosis beforeadministering the composition comprising 15-HEPE.

As used herein, “treating” or “treatment” of a disease, disorder, orcondition includes at least partially: (1) preventing the disease,disorder, or condition, i.e. causing the clinical symptoms of thedisease, disorder, or condition not to develop in a mammal that isexposed to or predisposed to the disease, disorder, or condition butdoes not yet experience or display symptoms of the disease, disorder, orcondition; (2) inhibiting the disease, disorder, or condition, i.e.,arresting or reducing the development of the disease, disorder, orcondition or its clinical symptoms; or (3) relieving the disease,disorder, or condition, i.e., causing regression of the disease,disorder, or condition or its clinical symptoms. The term “prevention”in relation to a given disease or disorder means: preventing the onsetof disease development if none had occurred, preventing the disease ordisorder from occurring in a subject that may be predisposed to thedisorder or disease but has not yet been diagnosed as having thedisorder or disease, and/or preventing further disease/disorderdevelopment if already present.

An “effective amount,” as used herein, refers to the amount of an activecomposition that is required to confer a therapeutic effect on thesubject. A “therapeutically effective amount,” as used herein, refers toa sufficient amount of an agent or a compound being administered whichwill relieve to some extent one or more of the symptoms of the disease,disorder, or condition being treated. In some embodiments, the result isa reduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, in some embodiments, an “effective amount” for therapeutic usesis the amount of the composition including a compound as disclosedherein required to provide a clinically significant decrease in diseasesymptoms without undue adverse side effects. In some embodiments, anappropriate “effective amount” in any individual case is determinedusing techniques, such as a dose escalation study. The term“therapeutically effective amount” includes, for example, aprophylactically effective amount. In other embodiments, an “effectiveamount” of a compound disclosed herein is an amount effective to achievea desired pharmacologic effect or therapeutic improvement without undueadverse side effects. In other embodiments, it is understood that “aneffect amount” or “a therapeutically effective amount” varies fromsubject to subject, due to variation in metabolism, age, weight, generalcondition of the subject, the condition being treated, the severity ofthe condition being treated, and the judgment of the prescribingphysician. The term “pharmaceutically acceptable” in the present contextmeans that the substance in question does not produce unacceptabletoxicity to the subject or interaction with other components of thecomposition.

Without further description, it is believed that one of ordinary skillin the art may, using the preceding description and the followingillustrative examples, make and utilize the agents of the presentdisclosure and practice the claimed methods and compositions. Thefollowing examples are intended to illustrate various embodiments of thepresent technology. As such, the specific embodiments discussed are notto be construed as limitations on the scope of the present technology.It will be apparent to one skilled in the art that various equivalents,changes, and modifications may be made without departing from the scopeof the present technology, and it is understood that such equivalentembodiments are to be included herein. Non-limiting examples ofcompositions comprising 15-HEPE that may be used with methods of thepresent technology are described herein. Further, all references citedin the disclosure are hereby incorporated by reference in theirentirety, as if fully set forth herein. The following working examplesare provided to facilitate the practice of the present disclosure, andare not to be construed as limiting in any way the remainder of thedisclosure.

EXAMPLE

A Phase I, single-centre, randomised, double-blind, placebo-controlledstudy in male and female healthy volunteers aged 18 to 45 years,inclusive was performed. Fifty-seven (57) subjects were enrolled with 8subjects per cohort (ideally 4 males and 4 females, but no less than 3per gender). Cohort 5 enrolled a total of 9 subjects to account fordiscontinued subjects. The effective date of study commencement wasdefined as inclusion of the first subject (inclusion starts with theinformed consent signature). Subjects who were enrolled in Part 1 of thestudy (single dose cohorts) could have been brought back and re-enrolledin Part 2 (multiple dose) provided they had no AEs related to the studydrug and that there was at least a 14-day washout period before startingthe multiple dose. There were 18 subjects who participated in both studyparts. The subjects underwent screening within 21 days prior to studyDay 1.

Part 1—Single Ascending Dose (SAD). Part 1 comprised 4 dose cohorts (100mg, 500 mg, 1000 mg, and 2000 mg). Six (6) subjects were randomized toreceive DS102 and 2 subjects received matching placebo. A single oraldose of DS102 or matching placebo was administered.

Part 1—Food Effect. Cohort 2 also received 500 mg of DS102 in 2 fedstates. While the first 500 mg dose was given in fasted state, thesecond and third 500 mg doses were given in fed state (standardATPIII/TLC diet and high-fat diet, respectively). The second dose wasreceived at least 14 days after their first dose and the third dose wasreceived at least 14 days after their second dose.

Part 2—Multiple Ascending Doses (MAD). Part 2 of the study involved amultipledose regimen at 3 dose levels using 3 cohorts consisting of 8subjects each. Six (6) subjects were randomized to receive DS102 and 2subjects received matching placebo. Cohorts 5 and 6 (9 and 8 subjects,respectively) received oral DS102 or placebo QD for 28 days.

Cohorts (for Part 1) commenced in a sequential manner starting with thefirst 3 cohorts (100 mg, 500 mg, and 1000 mg) in parallel with matchingplacebo. A minimum of 5 subjects with 8 days evaluable safety data fromthe 1000 mg cohort were required before the decision was made oncommencing to the next cohort (2000 mg single dose) and beforecommencing the first cohort in Part 2 (up to 500 mg/day).

A total of 49 subjects (32 subjects in Part 1(24 active and 8 placebo)and 17 subjects in Part 2 (13 active and 4 placebo)) entered the studyand were randomized to study treatment. A total of 47 subjects completedthe study. All subjects were included for safety analysis. All 37subjects who received DS102 were included in the PK analysis. Allsubjects enrolled in this study were judged by the PrincipalInvestigator (PI) to be normal, healthy volunteers who met all inclusionand none of the exclusion criteria.

In Part 1, DS102 capsules (Lot No. 2540M-1504) or matching placebo (LotNo. KM73) were administered in a single oral dose according to Table 1.

TABLE 1 Administration of DS102 and Placebo Capsules According toPart 1. Cohort DS102 Dose DS102 Dosage Fed/Fasted 1 100 mg 1 × 100 mgDS102 or Placebo Fasted Capsule 2 500 mg 1 × 500 mg DS102 or PlaceboFasted Capsules 3 1000 mg  2 × 500 mg DS102 or Placebo Fasted Capsules 42000 mg  4 × 500 mg DS102 or Placebo Fasted Capsules 2 500 mg 1 × 500 mgDS102 or Placebo Fed (Standard Capsules ATPIII/TLC Diet) 2 500 mg 1 ×500 mg DS102 or Placebo Fed (High Fat Capsules Diet)

In Part 2, DS102 capsules (Lot No. 2540M-1504) or matching placebo (LotNo. KM73) were administered QD for 28 days according to Table 2.

TABLE 2 Administration of DS102 and Placebo Capsules According to Part2. Cohort DS102 Dose DS102 Dosage Fed/Fasted 5  500 mg 1 × 500 mg DS102or Placebo Fasted Capsules QD 6 1000 mg 2 × 500 mg DS102 or PlaceboFasted Capsules QD 7 2000 mg 4 × 500 mg DS102 or Placebo Fasted CapsulesQD

Planned study duration for clinical conduct was 12 weeks. The totalduration of participation, including the screening period for eachsubject, was approximately 4 weeks for Cohorts 1, 3, and 4 and 7 weeksfor Cohort 2 in study Part 1. The total duration of participation,including the screening period for each subject, was approximately 9weeks for Cohorts 5 and 6 in study Part 2.

Pharmacokinetics: For study Part 1, Cohorts 1, 2, 3, and 4 blood sampleswere taken predose on Day 1 up to 312 hours postdose. For study Part 2,Cohorts 5, 6, and 7 blood samples were taken on Days 1, 14, and 28 atpredose and up to 168 hours postdose. The appropriate PK parameters,e.g., Cmax, Tmax, AUC0-24, AUC0-last, AUC0-inf, AUC % ext, Kel, t½,RCmax, and RAUC were presented, where appropriate. Plasma 15(S)-HEPEdata contained many values below the limit of quantitation (BLQ) andonly sparse measurable concentrations leading to incomplete PK profiles.Given the nature of the data observed, conventional dose proportionalityand steady-state analyses could not be performed. No inferentialstatistical analyses were performed for PK parameters.

Statistical Methods: Summary statistics, including sample size (N),arithmetic mean (mean), standard deviation (SD), coefficient ofvariation (CV %), median, minimum, and maximum were calculated for allnominal concentration time points. Plasma 15(S)-HEPE PK parameters weretabulated by treatment and listed by subject and parameter. Summarystatistics (N, mean, SD, CV %, median, minimum, and maximum) werecalculated for plasma 15(S)-HEPE PK parameters. In addition, geometricmean (Geom. Mean) and geometric CV % (Geom. CV %) were presented forAUCs and Cmax. Excluded subjects were included in the PK parameter tablelistings, but were excluded from the summary statistics and noted assuch in the tables. Mean and individual concentration-time profiles werepresented on linear and semi-log scales. Linear mean plots werepresented with and without SD. Individual plots were presented on linearand semi-log scales.

Safety: All clinical safety data were presented in by-subject datalistings. Safety was evaluated by clinical laboratory tests, physicalexamination, vital signs, electrocardiograms (ECGs), and adverse events(AEs).

Continuous variables were summarized using number of observations (N),mean, SD, median, minimum, and maximum. Frequency counts were reportedfor categorical data. AEs were classified according to the MedicalDictionary for Regulatory Activities (MedDRA®), Version 18.0.Concomitant medications were classified according to the World HealthOrganization (WHO) Drug Dictionary 1 Mar. 2015. Vital sign, ECG, andlaboratory summary and change from baseline results were presented.Shift tables were also presented for laboratory and ECG parameters.

Mean plasma concentrations of 15-Hydroxy-Eicosapentaenoic Acid EthylEster [15(S)-HEPE] following a single oral dose of 100 mg, 500 mg, 1000mg, and 2000 mg DS102, under fasted conditions, are presented in FIG. 1.

Concentration-time profiles of 15(S)-HEPE in plasma were not wellcharacterized following single oral administration of 100 mg, 500 mg,1000 mg, or 2000 mg DS102 under fasted conditions. Plasma concentrationsfollowing 100 mg DS102 were BLQ over the entire sampling interval, forall subjects. Only 2 subjects had quantifiable plasma concentrationsfollowing 500 mg DS102, 3 subjects following 1000 mg, and 4 subjectsfollowing 2000 mg (of which 1 had only 1 measurable concentration). Meanplasma concentrations were highly variable.

Mean plasma 15(S)-HEPE concentrations following a single oral dose of500 mg DS102 under fasted and fed conditions, are presented in FIG. 2.

When 500 mg of DS102 was administered with a standard or high-fat diet,concentration-time profiles of 15(S)-HEPE in plasma were characterizedfor all subjects. Mean plasma concentrations of 15(S)-HEPE were higherunder fed conditions compared to fasted conditions. Peak meanconcentrations were reached at approximately 4 hours following 500 mgDS102, with a standard or high-fat diet, followed by an apparently rapiddecline with plasma concentrations that remained quantifiable in atleast one subject for 12 hours postdose. There was no significantdifference between 15(S)-HEPE profiles from subjects on a standard orhigh- fat diet, but results were also considerably variable. Mean plasma15(S)-HEPE concentrations following multiple oral QD doses of 500 mg and1000 mg for 28 days, under fasted conditions, at days 1, 14, and 28 arepresented in FIGS. 3, 4, and 5, respectively.

Concentration-time profiles of 15(S)-HEPE in plasma were not wellcharacterized following multiple oral QD doses of 500 mg and 1000 mgDS102 for 28 days; mean plasma concentrations remained highly variable.Following 500 mg DS102 QD, mean plasma 15(S)-HEPE concentrations werehighly variable, but generally similar for all days. Predose values(troughs) were not quantifiable on Days 14 and 28. Peak mean 15(S)-HEPEconcentrations tended to increase with study day from 4 hours on Day 1to 6 hours on Days 14 and 28, followed by an apparently rapid decline,with plasma concentrations that remained measurable in at least onesubject through 12 hours postdose on Days 1 and 28 and through 24 hourspostdose on Day 14. Following 1000 mg DS102 QD, mean plasma 15(S)-HEPEconcentrations were higher on Day 14 than on Days 1 and 28. There wereno quantifiable predose values (troughs) on Days 14 and 28. Time to peakmean concentrations ranged from 4 to 6 hours, with plasma 15(S)-HEPEconcentrations that remained quantifiable in at least one subjectthrough 8 hours postdose on Days 1 and 28 and through 12 hours postdoseon Day 14. These results are presented in Table 3.

TABLE 3 Pharmacokinetic Parameters Following More Than One Dose ofDS102. Pharmacokinetic 100 mg Fasted 500 mg Fasted 1000 mg Fasted 2000mg Fasted Parameters (N = 0) (N = 2) (N = 3) (N = 3) AUC0-24 (ng *hr/mL)^(a) — — — — AUC0-last (ng * hr/mL)^(a) —  1270 (70.9)  1063(102.6)  733.3 (56.5) AUC0-inf (ng * hr/mL)^(a) — — — — AUC % extrap(ng * hr/mL)^(b) — — — — Cmax (ng/mL)^(a) — 343.7 (52.1) 366.2 (102.5)294.3 (70.1) Tmax (hr)^(c) — 6.005 (6.00, 6.01) 5.996 (5.99, 6.00) 8.001(6.01, 8.01) Tlast (hr)^(c) — 8.001 (8.00, 8.00) 7.999 (8.00, 8.00)8.001 (8.00, 8.01) Kel (l/hr)^(b) — — — — t½ (hr)^(b) — — — — 100 mgDS102 fasted on Day 1 500 mg DS102 fasted on Day 1 1000 mg DS102 fastedon Day 1 2000 mg DS102 fasted on Day 1 ^(a)Presented as geom. mean(geom. CV %) ^(b)Presented as mean ± SD ^(c)Presented as median(minimum, maximum) —: Not reportable. PK parameters were not calculablefor any subject following 100 mg Fasted. PK parameters were notcalculable for Subjects 9, 12, 15, and 16 following 500 mg Fasted. PKparameters were not calculable for Subjects 20, 23, and 24 following1000 mg Fasted. PK parameters were not calculable for Subjects 29, 31,and 32 following 2000 mg Fasted.

As shown in Table 3, the median Tmax values were 6.00 hours for both the500 mg and 1000 mg dose levels and 8.00 hours for the 2000 mg doselevel. For all 3 cohorts in the fasted state, PK parameters were onlycalculated for the 2 or 3 subjects with sufficient data. Exposureparameters (Cmax and AUC0-last) were highly variable and should beinterpreted with caution, with geometric mean coefficient of variation(CV %) above 50%.

TABLE 4 Pharmacokinetic Parameters Following a Single Dose of DS102. 500mg 500 mg 500 mg Pharmacokinetic Fasted Fed Standard Diet Fed High FatDiet Parameters (N = 2) (N = 6) (N = 6) AUC0-24 (ng * hr/mL)^(a) — 10940(17.9) — AUC0-last (ng * hr/mL)^(a) 1270 (70.9) 8450 (67.7) 9693 (51.9)AUC0-inf (ng * hr/mL)^(a) — 11050 (19.7) — AUC % extrap (ng * hr/mL)^(b)— 7.543 ± 9.7728 — Cmax (ng/mL)^(a) 343.7 (52.1) 2420 (62.1) 2402 (64.7)Tmax (hr)^(c) 6.005 (6.00, 6.01) 4.014 (2.00, 6.01) 6.021 (4.00, 7.99)Tlast (hr)^(c) 8.001 (8.00, 8.00) 8.017 (8.00, 12.00) 11.993 (8.00,12.01) Kel (l/hr)^(b) — 0.4711 ± 0.22828 — t½ (hr)^(b) — 1.998 ± 1.5155— 500 mg DS102 fasted on Day 1 500 mg DS102 fed-standard diet on Day 1500 mg DS102 fed-high fat diet on Day 1 ^(a)Presented as geom. mean(geom. CV %) ^(b)Presented as mean ± SD ^(c)Presented as median(minimum, maximum) —: Not reportable. PK parameters were not calculablefor Subjects 9, 12, 15 and 16 following 500 mg Fasted.

As shown in Table 4, the median Tmax values following single-doseadministration of 500 mg DS102 after a standard and high-fat diet were4.00 hours and 6.00 hours, respectively. For both treatment regimens, PKparameters were calculated for the 6 subjects who received DS102, exceptfor AUC0-inf and t½ which were calculable for only 4 subjects followinga standard diet.

As shown in Table 5, following a standard diet, the mean 15(S)-HEPE t½was 2.00 hours. No clear elimination phase was apparent following ahigh-fat diet. Though data were highly variable, it was apparent that astandard or high-fat diet increased mean maximum and overall exposure of15(S)-HEPE (based on Cmax and AUC0-last, respectively) relative to thefasted condition. Moreover, 15(S)-HEPE exposure following a single oraldose of 500 mg DS102 appeared higher under fed conditions relative tohigher doses (1000 mg and 2000 mg) under fasted conditions. Compared towhen DS102 was given with a standard diet, the apparition of 15(S)-HEPEin plasma given with a high-fat diet was delayed by 2 hours. Due to thehigh variability, it was not possible to determine if the extent ofexposure was different following a high-fat versus standard diet usingnoncompartmental methods.

TABLE 5 Pharmacokinetic Parameters at Days 1, 14, and 28. 500 mg QD -Fasted Pharmacokinetic Day 1 Day 14 Day 28 Parameters (N = 6)* (N = 3)(N = 2) AUC0-24 (ng * hr/mL)^(a) 6249 — — AUC0-last (ng * hr/mL)^(a)1681 (156.6) 2370 (106.8) 2787 (92.6) AUC0-inf (ng * hr/mL)^(a) 6277 — —AUC % extrap (ng * hr/mL)^(b) 9.411 — — Cmax (ng/mL)^(a) 459.1 (119.5)644.1 (68.3) 737.4 (67.9) Tmax (hr)^(c) 5.005 (4.00, 8.14) 5.995 (5.99,6.01) 6.004 (6.00, 6.01) Tlast (hr)^(c) 8.079 (6.00, 12.00) 8.034 (8.00,12.00) 10.002 (8.01, 12.00) Kel (l/hr)^(a) 0.2455 — — t½ (hr)^(a) 2.824— — RAUC^(b) — 6.807 ± 10.322 8.205 ± 10.210 RCmax^(b) — 4.177 ± 5.40555.923 ± 6.8329 500 mg DS102 QD fasted on Days1-28 ^(a): Presented asgeom. mean (geom. CV %) ^(b): Presented as mean ± SD ^(c): Presented asmedian (minimum, maximum) —: Not reportable. *AUC0-24, AUC0-inf, AUC %extrap, Kel, and t½ were reported only for Subject 38. PK parameterswere not calculable for Subjects 34, 37, and 39 on Day 14. PK parameterswere not calculable for Subjects 34, 37, 39, and 138 on Day 28.

Safety Results. There were no deaths, serious adverse events (SAEs), orsubject discontinuations due to AEs reported in this study. No trend wasobserved in single or multiple ascending doses of DS102 with regard tosubject incidence for AE reporting and was comparable to AE reportingfollowing placebo. The PI considered the majority of events to be mildin intensity and not related to the study treatment. The majority of theevents reported were considered not related to the study treatment withevents of dysguesia and eructation (following DS102 treatment)considered related. There were several laboratory events reported as AEsduring the study in Parts 1 and 2. All laboratory reported events weremild in intensity and considered not related to the study treatment.

Single ascending doses of 100 mg, 500 mg, 1000 mg and 2000 mg DS102 andmultiple ascending doses of 500 mg, 500 and 1000 mg were safe and welltolerated in the healthy subjects in this study.

PK profiles of 15(S)-HEPE in healthy subjects following single oraladministration of 100 mg, 500 mg, 1000 mg, or 2000 mg DS102 andfollowing multiple oral QD administration of 500 mg or 2000 mg DS102 inthe fasted state could not be well characterized due to the lack ofquantifiable concentrations and variability.

Administration of DS102 in a fed state (standard or high-fat diet)appeared to considerably increase 15(S)-HEPE absorption.

The terminal elimination phase was generally not apparent followingsingle and multiple doses in the fasted state. Mean t½ w estimated to be2.0 hours in subjects who received a standard diet.

Results across dose levels studied in the single and multiple dosecohorts are not indicative of a predictable exposure, one that increasesproportionally with increasing dose.

This disclosure is not intended to be exhaustive or to limit the presenttechnology to the precise forms disclosed herein. Although specificembodiments are disclosed herein for illustrative purposes, variousequivalent modifications are possible without deviating from the presenttechnology, as those of ordinary skill in the relevant art willrecognize. In some cases, well-known structures and functions have notbeen shown and/or described in detail to avoid unnecessarily obscuringthe description of the embodiments of the present technology. Althoughsteps of methods may be presented herein in a particular order, inalternative embodiments the steps may have another suitable order.Similarly, certain embodiments of the present technology disclosed inthe context of particular embodiments can be combined or eliminated inother embodiments. Furthermore, while advantages associated with certainembodiments may have been disclosed in the context of those embodiments,other embodiments can also exhibit such advantages, and not allembodiments need necessarily exhibit such advantages or other advantagesdisclosed herein to fall within the scope of the present technology.Accordingly, this disclosure and associated technology can encompassother embodiments not expressly shown and/or described herein.

Throughout this disclosure, the singular terms “a,” “an,” and “the”include plural referents unless the context clearly indicates otherwise.Similarly, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the terms “comprising” and the like are used throughout this disclosureto mean including at least the recited feature(s) such that any greaternumber of the same feature(s) and/or one or more additional types offeatures are not precluded. Reference herein to “one embodiment,” “anembodiment,” or similar formulations means that a particular feature ofa composition, a composition, a method, or a characteristic described inconnection with the embodiment can be included in at least oneembodiment of the present technology. Thus, the appearances of suchphrases or formulations herein are not necessarily all referring to thesame embodiment. Furthermore, various particular features, compositions,methods, or characteristics may be combined in any suitable manner inone or more embodiments.

From the foregoing, it will be appreciated that specific embodiments ofthe invention have been described herein for purposes of illustration,but that various modifications may be made without deviating from thescope of the invention. Accordingly, the invention is not limited exceptas by the appended claims.

What is claimed is:
 1. A pharmaceutical composition comprising 15-HEPEor a pharmaceutically acceptable derivative thereof.
 2. The compositionof claim 1, wherein the pharmaceutical composition comprises100 mg to1000 mg of 15-HEPE or a pharmaceutically acceptable derivative thereof.3. The composition of claim 1, wherein the pharmaceutically acceptablederivative thereof comprises an ester, a conjugate, a salt, or acombination thereof.
 4. The composition of claim 1, wherein the 15-HEPEis in free acid form.
 5. The composition of claim 1, wherein the 15-HEPEis in esterified form.
 6. The composition of claim 5, wherein theesterified form is a methyl ester form, an ethyl ester form, or acombination thereof.
 7. The composition of claim 5, wherein theesterified form is a triglyceride form.
 8. The composition of claim 1,wherein the 15-HEPE is in salt form.
 9. The composition of claim 1,wherein the 15-HEPE (1) comprises 15(S)-HEPE and/or 15(R)-HEPE, (2)consists of 15(S)-HEPE or (3) consists of 15(R)-HEPE.
 10. A method oftreating a disease in a subject in need thereof, the method comprisingadministering to the subject an effective amount of a compositioncomprising 15-HEPE or a pharmaceutically acceptable derivative thereof.11. The method of claim 10, wherein the disease is selected from thegroup consisting of impaired insulin sensitivity, psoriasis, fibrosis,cancer, neurodegenerative disorders, inflammatory diseases, adipocytedifferentiation, fertility or reproduction issues, pain, and obesity.12. The method of claim 11, wherein the cancer is a skin cancer.
 13. Themethod of claim 12, wherein the skin cancer is melanoma.
 14. The methodof claim 11, wherein the neurodegenerative disorder is Huntington'sdisease.
 15. The method of claim 11, wherein the fibrosis is idiopathicpulmonary fibrosis.
 16. The method of claim 10, wherein thepharmaceutically acceptable derivative thereof comprises an ester, aconjugate, a salt, or a combination thereof.
 17. The method of claim 10,wherein the disease is reduced in comparison to a second subject who hasnot been administered the composition, and optionally, has beenadministered a placebo.
 18. The method of claim 10, wherein theeffective amount of the composition comprising 15-HEPE or apharmaceutically acceptable derivative thereof is between about 100 mgto about 2000 mg.
 19. A method of increasing absorption of 15-HEPEcomprising, administering a composition comprising 15-HEPE or derivativethereof to a subject in need thereof that is in a fed state.
 20. Themethod of claim 19, wherein the pharmaceutically acceptable derivativethereof comprises an ester, a conjugate, a salt, or a combinationthereof.